Compounds labeled with positron-emitting isotopes 18F and 11C have found powerful applications as tracers for positron emission tomography (PET). These molecular probes have become indispensable for understanding the mechanisms of both normal brain function and brain disorders. Due to the short half-lives of these radioisotopes, the synthesis and purification of 18F- and especially 11C-tracers must be performed with extreme rapidity if they are to retain sufficient radio-emitting properties to be useful as imaging agents. Thus the growth of the PET technique has been closely tied to the development of new rapid-synthesis and purification methods. In this revised proposal, we outline a paradigm shift in radiosynthesis methodology by focusing on the development of a new class of reactive entities that are uniquely activated by metal cations that form part of the nuclide salts most often used in the synthesis of PET agents (e.g. K18F and K11CN). This new reactive system termed nucleophile assisting leaving group (NALG) is expected to significantly expedite the radiosynthesis of imaging agents and limit side-product formation. In our proposed approach, a PET tracer precursor is covalently attached to a polymer support that has been modified to contain the new reactive entity (the NALG). In a second step, cyclotron-derived fluoride or cyanide are added to the polymer resulting in the formation of the desired radio labeled tracer as the only product. In addition to increased reaction rates, this unprecedented strategy has been designed to avoid byproduct formation and minimize the time required for reaction purification. Taken together, these reaction improvements are expected to leave more time for the synthesis of imaging probes with potentially higher specific activities and greater molecular complexity than previously possible. We will employ this new NALG polymer method in the first synthesis of [11C]baclofen, a 3- amino-butyric acid (GABA) receptor agonist. As a well known probe for targeting GABAB, baclofen is widely- used for the management of spasticity exhibited in multiple sclerosis, Tourette syndrome, and dystonia. Made possible by the new polymer-based method, the efficient radio synthesis of [11C] baclofen (and related analogs for better brain permeation) is expected to facilitate future PET studies of GABA receptors and ultimately lead to improved therapies for diseases related to these receptors. PUBLIC HEALTH RELEVANCE: This proposed study introduces new chemistry to significantly improve current methods used to make PET medical imaging compounds thus allowing this imaging technique to be more widely available. Two novel compounds will be targeted to further medical researchers' understanding of brain function in the epileptic and multiple sclerosis patient.